Z-methyl -



lit

United States Patent() Z-METHYL 4 AMINO 5 ACETAMINOMETHYL- PYRIMIDINEAND PROCESS FOR ITS PRODUC- 2,775,592 Patented Dec. 25, 1956manufactured as follows:

- 1. Condensation of ethoxymethylene malonedinitrile TION 5-withiacetarnidine (Japanese Patent No; 143,065); or by I 2. Obtaining 2methyl-4-hydroXy-5-cyanopyrimid1ne Akita Takamizawa, Kuise, Amagasaki,Japan, assignor t0 by condensation of acetimidoether with aaaminomethyl-Shinogi & (10., Ltd., Osaka, Dosho-machi, 'Higashi-kll, ene-cyanoacetateor acetam-idine with a-ethoxymethylene- Japan cyano acetate, thereafterchlorinating and aminating the above intermediate. (Todd, .B-ergel;ibid. I apanese N Drawmg' ggg fie gggsfi 1953 Patent No. 14,324.) Suchprocedures take a substantial amount'of time for completion and requirethe exercise 5 Claims- 260-2564) of careful control measures.

On the other hand, the procedures of Group II are This invention relatesto the novel compound Z-methyl- ;even longer than those of Group I andinvolve many 4 amino-5-acetaminomethylpyrimidine and to a processdiificult reactions. 1 for preparing the same. More particularly, theinvention I have discovered that u-alkoxymethylene-p-alkoxycontemplatesthe provision of a process for the producpropionitrile which can beobtained by alkylation .of tion of this compound involving thecondensation of 5- alkali metal salt of a-formyl-fi-.alkoxypropionitrileexists alkoxy-aaalkoxymethylenepropionitrile with acetamidine. in twoisomeric forms. For example, in methylating with2-methyl-4-ammo-5-aminomethylpyrimidine is an im- .dimethyl-sulfateNa-enolate of a-forrnyl-B-ethoxypropiolportant compound and is used asan intermediate in the nitrile which is derived fromfi-ethoxypropionitrile by .m prepanation of vitamin B1 (thiaminehydrochloride). In ,formylation with sodium ethylate and ethylform-atein the past, various methods have been employed in atabsolute benzene, aliquid of boiling point 103104C. tempt-ing to produce this compound.These known at 3mm. mercury, an isomeric form hereinafter refer-redprocedures are generally classified to two main groups; to as (A) isobtained in 90% yield. When the above one involving the reduction of2-methyl-4-amino-5- reaction is carried out in an aqueous methanolsolution, cyanopyrimidine, and the other involving the transform-athereaction tends to produce an isomeric form compristion of4,5-substituents of 2-methyl-4-substituted pyrimiing a liquid of boilingpoint 94-96 C. at 3 mm. mercury, dine-S-acetic acid derivatives. Thesesyntheses may be hereinafter referred to as (B). Furthermore, when thefurther subdivided as follows: former reaction mixture is reacted withsodium hydroxide for several hours, isomeric form (B) is obtained inGroup. I (Reducnon of 'gl g '4' T l m" 90% yield. Moreover, whenisomeric form (A) is i i I treated with sodium hydroxide in absolute oraqueous Catalytic reduction: Todd, Bergel; Chem- 300-, equi-volumemixture of ethanol and methanol, isomeric 364 (193 7 Grewe; Z. Physiol.Chem. 242, 89 (1937). form (A) is theoretically converted into isomericform Japanese Patents Nos. 141,330, 168,968, and 172,429. (B). Elementalanalytical data of (A) and (B) corre- (ii) Electrolytic reduction..(This is a sort of catalytic spond to the empirical formula C'7H1102N.According reduction and not substantially difielen-t from the to Zeiselsmethod, they show the existence of amethoxyl above. The reduction isperformed in the liquid phase.) 40 group and an ethoxyl group.Therefore, it is obvious 131119111636 Patents that both of the isomericforms havethe composition .Group II (Transformation of 4,5-substituentof 2- 1 P a'methoxymfithylene p P The methyl-4-substituted pyrimidine5-acetic acid derivainfra-red absorption spectrum show absorption bandsfor 171;) p (A) occurring at 4.55 1. and 6.11 and for (B) occurring l at4.54 and 6.09 4. Thus, it is obvious that both isomeric (1-11)Chorinatlon, acidamlnation and Holfmanns deforms have and unsaturatedbonds i t'f fii digmfdation From the fact that their dipolemoments are=4.90D 1 i 1 i (A) and 3.911) (B) respectively, it is known that in bothchlormanon ammimon and y i i of of the geometrical isomers (A) is thecis form and (B) i g ifig ggggi' gg gg gi 23 352 5 2325; d Hofi is thetrans form of a-methoxymethylene-B-ethoxypromanns decomposition of2-methyl-4-hydroxy-S-carbethplommle as shown by the following formulae'oxymethylpyrimidine. (Described in Andersag, Viest- EtOCH -O-ONEtO-OIEb-(k-CN phal; Ben, 70, 2035 (1937).) British Patents os. 456,571and 471,416. H C 00113 (Ham) 0 H In these prior methods, the synthesesof Group I are The physical constants of the homologues ofu-alkoxyunsatisfaotory because of the fact that the reactions aremethylene p alkoxypropionitrile are shown in the folgreatly influencedby the presence of even slight imlowing table. purities in thecyanopyrimidine starting materials, and ROCHZ C CN precious metals, suchas palladium, platinum, and gold, I are required as catalyst. Moreover,the procedures CHOR R R Ois- Boiling Point Specific Weight Index ofRefraction Trans CH4 CH3 $5393 8333521 353131: ii i ii i itiifiofiilifii 103104 0.,amm. Hg (11 099290 nD =1A5so (EH5 CH3 94-9e=0., 3 mm. Hg.--" 111 198240 nn =r42ss Cls- 109-110 0., 2mm. Hg d40.9813O ns =L4580 104-1os 0., 3 mm. Hg (14 "0.96357 nD ==L4240 104-107"0., 2 mm. Hg (1, 0.98183 nD =L4575 CH3 107109C.,3mm.Hg di 0.96527 7L|2C=L4280 147-129 0.,4mm. Hg di 0.95250 n,, =1.4550 Trans-. 109-1120.,4mm. Hg 114 094976 m q=r4370 The condensation of cis aalkoxymethylene 3- alkoxypropionitrile with acetamidine yields 2 methyl-4 amino 5 alkoxymethylpyrimidine. The condensation of trans ualkoxymethylene ,8 alkoxypropionitrile with acetamidine yieldscolorless, dice-like crystals of melting point, 203204 C. As a result offurther investigations, this compound was identified as 2-methyl- 4amino 5 acetaminomethylpyrimidine. It is believed that this compound isnovel and has not been reported heretofore in the literature. All of thehomologues of a alkoxymethylene I8 alkoxypropionitrile when used in theabove reaction yield 2 methyl 4 amino- 5 alkoxymethylenepyrimidine. Itis to be noted that the term alkoxy as used herein is intended toinclude aliphatics and aralkoxy, substituents which are similar toaliphatic alkyl substituents.

The reaction of the invention may be performed with or without a solventwhich dissolves both acetamidine and a alkoxymethylene Balkoxypropionitrile. The solvents which may be used are those chosenfrom the group consisting of lower aliphatic alcohols, such as methanol,ethanol and propanol or mixtures of one or more of these solvents withbenzene, toluene and petroleum ether. Furthermore, although the use of acondensing agent is desirable for purposes of acceleratingdealcoholization, such, use is not essential to the successful operationof the process. In practice, the use of an alkali substance in excess ofequimolecular proportions will affect this result, and, when alkalisubstances such as the alkali metals and alkaline earth metal hydroxidesor carbonates are employed the reaction may be affected at lowtemperatures.

The intermediate of melting point 104-106 C. (needles) was obtained inthis reaction. The substance is /2 mole of innermolecular water and itsdehydrate and picrate melts at l72l73 C. and 202203 C., respectively.The latter exhibit prism or dice-like crystal formations.

The intermediate is found to be identical with that obtained as thecondensation product of 2 methyl 4- amino-S-aminomethylpyrimidine withacetimidoether. As the result of my investigations, this intermediatewas identified as 2,7 dimethyl 5,6 dihydropyrimido (4,5- d)pyrimidine.Moreover, upon condensing cis u. alkoxymethylene ,8 alkoxypropionitrilewith acetamidine in methanolic solution, 2 methyl 4 amino 5-acetaminomethylpyrimidine is obtained as the primary product and a traceof 2 methyl 4 amino 5 alkoxymethylpyrimidine is also obtained.

It is believed that this phenomenon occurs by reason I of thetransformation of the cis-nitrile to the trans-nitrile under action ofthe solvent system. In short, the reaction of c alkoxymethylene ,8alkoxypropionitrile with acetamidine was not predictable from anypreviously known syntheses. -With respect to the mechanism of thereaction, it is believed that the following occurs: the ;3-position ofthe trans-nitrile of Formula I below is substituted with one mole ofacetamidine, with the formation of a-acetamidinomethylene of EquationII, but ringclosure does not occur since the substituent is present inthe trans-position against -CEN bond. In the case of the cis-nitrile,ring-closure occurs immediately with the production of 2 methyl 4 aminoalkoxymethylpyrimidine.

In the course of the above reaction the a ethoxyl of Formula II isfurther substituted with a mole of acetamidine and is closed to thepyrimidine ring, Formula III,

and the 4 amino radical of the pyrimidine condenses with the remainingacetamidino radical to produce the intermediate 2-7 dimethyl 5,6dihydropyrimidino(4,5- d)pyrimidine, Equation I-V.

At the end of the continuous reaction, the compound of Formula IV ismoderately autohydrolized to Z-methyl- 4 amino 5.acetaminomethylpyrimidine, Formula V.

wherein, R, R equal alkyl, aralkyl.

The reaction is characterized by extreme smoothness and high purity ofthe resultant pro-duct; in particular, the product of the lowtemperature reaction following addition of excessive alkali isremarkably pure.

The product 2-methyl-4-amino-5-acetaminopyrimidine of the invention isreadily hydrolized to 2-methyl-4-amino- S-aminomethylpyrimidine withtheoretical yields and may be converted to2-methyl-4-acetamino-5-acetaminomethylpyrimidine by acylation.

Summarizing the foregoing, it will be seen that the process of theinvention is characterized by 1) the use of inexpensive raw materials,(2) speed of reaction, (3) smoothness of reaction, and (4) high purityof end product. The end product is, of course, valuable for use in themanufacture of aminomethylpyrimidine.

The process of the invention is illustrated by the following examples,which are offered by way of illustration only and not with the intent oflimiting the scope of the invention.

Example 1.-33.'5 g. of 'acetamidine hydrochloride (crystalline) wereadded to a sodium methylate solution formed of 90 cc. of absolutemethanol and 8 g. of metallic sodium. The mixture was agitated for 30minutes at room temperature, neutralized and then heated at -70 C. Tothis mixture, 19 g. of trans-a-methoxymethylene- ,3-methoxypropionitrilewere titrated and the reaction mixture was refluxed on boilingwater-bath for 2 hours. Thereafter the reactant was allowed to standwhereby sodium hydrochloride is removed. Methanol is removed from thereactant solution by distillation and the crystallike residue was heatedwith sodium hydroxide solution (1 g. of sodium hydroxide in 30 cc. ofwater) on boiling water-bath for 1 hour. The reactant was adjusted to pH6.8 with acetic acid and allowed to stand.

Colorless dice-like crystals were obtained. Furthermore, by :salting outthe mother liquor, further quantities dissolved in a mixture of 200 cc.of alcohol and 15 cc.

of hydrochloric acid (20%). To this mixture gaseous hydrochloric acid isadded to the heated solution on water-bath.2-methyl-4-amino-5-aminomethylpyrimidine is gradually precipitated fromthe reaction mixture in crystalline form. The crystals melt at 265 C.(decomposition method) and is found to be identical with authentic2-methyl-4-amino-5-aminomethylpyrimidine hydrochoride.

Example 2.--By using 19 g. ofcis-a-methoxymethylenefl-methoxypropionitrile in the process of Example1, the reaction yields 2-methyl-4-amino-5-acetylaminomethylpymimidine.The compound melts at 203*204 C. Yield, 17 g., 60%.

Example 3.-By using 21.1 g. oftrans-a-methoxymethylene-p-ethoxypropionitrile in the process of Example1, the reaction yields Z-methyl-4-amino-5-acetylaminomethylpyrimidine.The compound melts at 203-204 C. Yield, 17 g., 60%.

Example 4.--By using 11 g. oftrans-u-benzyloxymethylene-fi-ethoxypropionitrile, 12 g. of acetamidinehydrochloride, 2.7 g. of metallic sodium, and 30 cc. of methanol in theprocess of Example 1, the reaction yields 5.6 g. of2-methyl-4-amino-5-acetaminomethylpyrimidine. Yield, 58%.

Example 5 .-21.7 g. of acetarnidine hydrochloride were added to sodiumethylate solution formed from 70 cc. of methanol and 6.4 g. of metallicsodium. The mixture was cooled on the ice-bath and agitated for 30minutes during cooling. To this mixture, 14.1 g. ofB-ethoxy-otmethoxymethylenepropionitrile (Formula I, above) were addedand the mixture was further agitated for 12 hours. By passing 1.7 g. ofgaseous chlorine into the reaction solution, the excess of alcoholatewas resolved and sodium hydrochloride filtered off. The solvent wasdistilled off and the crystal-like residue heated with 30 cc. of wateron boiling water-bath for 3 hours. The reactant was permitted to standfor a short period and 2-methy1-4- amino-5-acetaminomethylpyrimidine wasobtained in crystalline form. Further quantities of the compound wereobtained by salting out the mother liquor in the same 6 manner as inExample 1. The yield was of theoretical.

Having thus described the invention, what it is desired to secure byLetters Patent is:

1. Process for the production of 2-methy1-4-amino-5-acetaminomethylpyrimidine which comprises reacting ana-alkoxymethylene-p-alkoxypropionitrile with acetamidine and recoveringsaid 2-methyl-4-amino-S-acetaminomethylpyrimidine as the reactionproduct.

2. Process for the production of 2-methyl-4-amino-5-acetaminomethylpyrimidine which comprises reacting acis-a-alkoxymethylene-fi-alkoxypropionitrile with acetamidine andrecovering said 2-methyl-4-amino-5-acetaminomethylpyrimidine as thereaction product.

3. Process for the production of 2-methyl-4-amino-5-acetaminomethylpyrimidine which comprises reacting ane-alkoxymethyleneqfi-alkoxypropionitrile with acetamidine .in an organicsolvent system, and separating and recovering said2-methyl-4-amino-5-acetaminomethylpyrimidine from the reaction mixture.

4. Process as claimed in claim 3 wherein the compound 2,7-dimethyl-5,6-dihydropyrimido(4,5-d) pyrimidine is ob tained as an intermediateduring the reaction.

5. The chemical compound2,7-dimethyl-5,6-dihydropyrimido(4,5-d)pyrimidine, represented by theformula:

(Ill-OH: N

obtained as an intermediate in the reaction of ana-alkoxymethylene-p-alkoxypropionitrile with acetamidine for theproduction of 2-methyl-4-amino-5-acetaminomethylpyrimidine.

References Cited in the file of this patent UNITED STATES PATENTS2,184,720 Matukawa et a1. Dec. 26, 1939 FOREIGN PATENTS 819,596 FranceOct. 21, 1937

1. PROCESS FOR THE PRODUCTION OF 2-METHYL-4-AMINO-5ACETAMINOMETHYLPRIMIDINE WHICH COMPRISES REACTING AN A-ALKOXYMETHYLENE-B-ALKOXYPROPIONITRILE WITH ACETAMIDINE AND RECOVERING SAID 2-METHYL-4-AMINO-5-ACETAMINOMETHYLPRIMIDINE AS THE REACTION PRODUCT.
 5. THE CHEMICAL COMPOUND 2,7-DIMETHYL-5,6-DIHYDROPYRIMIDOL(4,5-D)PYRIMIDINE, REPRESENTED BY THE FORMULA: 